Nine controversial questions about augmentation therapy for alpha-1 antitrypsin deficiency: a viewpoint.

Augmentation therapy with intravenous alpha-1 antitrypsin is the only specific treatment for alpha-1 antitrypsin deficiency (AATD)-associated emphysema. This treatment has been available and remained basically unchanged for more than 35 years, but many questions persist regarding its indications, regimen of administration and efficacy. Because AATD is a rare disease, it has not been possible to conduct randomised, placebo-controlled trials that are adequately powered for the usual outcomes analysed in non-AATD-related COPD, such as lung function decline, exacerbations, symptoms or quality of life. New outcomes such as lung densitometry measured by computed tomography are more sensitive for identifying emphysema progression but are not widely accepted by regulatory agencies. In addition, clinical manifestations, severity and the natural history of lung disease associated with AATD are very heterogeneous, which means that individual prediction of prognosis is challenging. Therefore, the indication for augmentation is sometimes a dilemma between initiating treatment in individuals who may not develop significant lung disease or in whom disease will not progress and delaying it in patients who will otherwise rapidly and irreversibly progress.Other areas of debate are the possible indication for augmentation in patients with severe AATD and respiratory diseases other than emphysema, such as bronchiectasis or asthma, and the use of therapy after lung transplant in AATD patients. All these uncertainties imply that the indication for treatment must be personalised in expert reference centres after in-depth discussion of the pros and cons of augmentation with the patient.

Long-term safety of Prolastin®-C, an alpha1-proteinase inhibitor, in Japanese patients with alpha1-antitrypsin deficiency.

BACKGROUND: Safety and pharmacokinetics (PK) of alpha1-proteinase inhibitor, modified process (Alpha-1 MP), was evaluated in a clinical trial of Japanese patients with alpha1-antitrypsin deficiency (AATD). The present study aimed to evaluate the long-term safety of weekly intravenous infusions of 60 mg/kg Alpha-1 MP in Japanese patients with AATD. METHODS: This was a multi-center, open-label extension (OLE) study that enrolled adult patients with AATD, who had completed the preceding safety and PK clinical trial. Patients were administered with Alpha-1 MP (60 mg/kg) weekly, for 52 weeks, and this could be renewed annually. Alpha1-MP trough levels (Cmin) were evaluated, and safety endpoints include: treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), TEAEs potentially related to Alpha-1 MP, chronic obstructive pulmonary disease (COPD) exacerbations, laboratory parameters, vital signs, and pulmonary function tests (forced expiration volume in 1 s [FEV1] and forced vital capacity [FVC]). RESULTS: Four patients underwent Alpha-1 MP intravenous infusions at a mean (SD) of 210.8 (9.54) for 213 weeks (four years), with a Cmin of 55.73 (4.99) mg/dL. A total of fifty-four TEAEs were reported in four patients, in which most of them were mild (n = 52, 96.3%). Two patients had five SAEs, and all were unrelated to treatment. Three mild TEAEs were potentially related to treatment with Alpha-1 MP. No clinically significant findings in laboratory parameters, COPD exacerbations, or vital signs were observed. There were no identifiable differences in FEV1 and FVC throughout the study period. CONCLUSIONS: Long-term weekly intravenous infusions of 60 mg/kg Alpha-1 MP are generally safe and well-tolerated in Japanese patients with AATD. CLINICALTRIALS: GOV: NCT02870348; JAPIC CTI: JapicCTI-163194.

Opinions and Attitudes of Pulmonologists About Augmentation Therapy in Patients with Alpha-1 Antitrypsin Deficiency. A Survey of the EARCO Group.

BACKGROUND: Augmentation therapy (AT) is the only specific treatment licensed for patients with alpha-1 antitrypsin deficiency (AATD) associated lung disease. Since patients with severe AATD may have a very different prognosis and AT requires intravenous infusions for life, the decision to initiate AT may be challenging. METHODS: This survey was conducted on 63 experts in AATD from 13 European countries about their opinions and attitudes regarding AT. Participants were asked to rank the importance of 11 identified factors related with the prescription of AT. In addition, each participant was asked to respond to the indication of AT for 30 out of 500 hypothetical cases developed with the combinations of the 11 factors. Each case was evaluated by 3 experts to check the concordance. RESULTS: The variables that scored higher on preferences for initiating AT were AAT genotype (score 8.6 from a Likert scale 0-10 (SD: 1.7)), AATD serum level (8.2 (SD:2.4)) and FEV1 (%) decline (7.9 (SD:2.4)). Among the 500 different cases, there was an agreement in indication of AT among the 3 experts in 291 (58.2%). Regarding the variables associated with AT, it was indicated to 81.9% of Pi*ZZ, 52.4% of Pi*SZ and 9.8% of Pi*MZ (p < 0.0001). For Pi*ZZ patients, multivariate analysis identified younger age, reduced FEV1 (%), higher FEV1 decline and worse emphysema as significantly associated with prescription (AUC = 0.8114); for Pi*SZ variables were younger age, worse FEV1 (%) and worse emphysema (AUC = 0.7414); and for Pi*MZ younger age, worse DLCO (%), higher DLCO decline and dyspnea (AUC = 0.8387). CONCLUSION: There is a high variability in the criteria for prescription of AT among European experts. Most cases were recommended AT according to guidelines, but a significant number of patients with genotype Pi*SZ and almost 10% Pi*MZ were recommended to initiate AT despite the lack of evidence of efficacy in these genotypes.

New Patient-Centric Approaches to the Management of Alpha-1 Antitrypsin Deficiency.

Alpha-1 antitrypsin deficiency (AATD) is a rare and underdiagnosed genetic predisposition for COPD and emphysema and other conditions, including liver disease. Although there have been improvements in terms of awareness of AATD and understanding of its treatment in recent years, current challenges center on optimizing detection and management of patients with AATD, and improving access to intravenous (IV) AAT therapy - the only available pharmacological intervention that can slow disease progression. However, as an orphan disease with geographically dispersed patients, international cooperation is essential to address these issues. To achieve this, new European initiatives in the form of the European Reference Network for Rare Lung Diseases (ERN-LUNG) and the European Alpha-1 Research Collaboration (EARCO) have been established. These organizations are striving to address the current challenges in AATD, and provide a new platform for future research efforts in AATD. The first objectives of ERN-LUNG are to establish a quality control program for European AATD laboratories and create a disease management program for AATD, following the success of such programs in the United States. The main purpose of EARCO is to create a pan-European registry, with the aim of understanding the natural history of the disease and supporting the development of new treatment modalities in AATD and access to AAT therapy. Going further, other patient-centric initiatives involve improving the convenience of intravenous AAT therapy infusions through extended-interval dosing and self-administration. The present review will discuss the implementation of these initiatives and their potential contribution to the optimization of patient care in AATD.

A Phase II, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study Evaluating the Efficacy and Safety of Alpha-1 Antitrypsin (AAT) (Glassia®) in the Treatment of Recent-Onset Type 1 Diabetes.

Our aim was to assess the efficacy, safety, and tolerability of alpha-1 antitrypsin (AAT) as a therapeutic modality for ß-cell preservation in patients with recent-onset type 1 diabetes. Seventy type 1 diabetes patients (37 males; mean age 13.1 ± 4.1years) were randomized to treatment with 22 infusions of AAT (Glassia®) (60 or 120 mg/kg) or placebo. The primary outcome was the area under the curve (AUC) of C-peptide from a 2-h mixed-meal tolerance test after 52 weeks. At week 52, C-peptide was 0.9, 0.45, and 0.48 pmol/mL in the AAT-120, AAT-60, and placebo groups (p = 0.170 and p = 0.866 vs. placebo, respectively). The declines in C-peptide glycated hemoglobin (HbA1c) and the total insulin dose (U/kg) were similar across groups. Within the predefined 12-18-years subgroup, the C-peptide AUC decreased significantly in the placebo and AAT-60 groups (-0.34 and -0.54 pmol/mL, respectively, p < 0.01), with a borderline decrease in the AAT-120 group (-0.29 pmol/mL, p = 0.047). The mean HbA1c level was significantly lower in the AAT-120 group compared to the placebo (6.7% ± 0.9% vs. 8.2 ± 1.4%, p = 0.05), and a higher percentage of patients attained HbA1c ≤ 7% (75% vs. 25%, p = 0.05). AAT was tolerated well, with a similar safety profile between groups. The AAT intervention showed promise in the subgroup of adolescents with recent-onset type 1 diabetes. Further studies are warranted to determine the impact and proposed mechanism of action of AAT in ß-cell preservation.

Comparison of the liquid and lyophilized formulations of Prolastin®-C for Alpha1-Antitrypsin deficiency: Biochemical characteristics, pharmacokinetics, safety and neoantigenicity in rabbits.

Multiple analytical and preclinical studies were performed to compare the biochemical characteristics, pharmacokinetics (PK), safety and neoantigenicity of a new 5% liquid formulation of Alpha-1 Proteinase Inhibitor (Liquid A1PI, Prolastin®-C Liquid) with the lyophilized version (Lyophilized A1PI, Prolastin®-C). Liquid A1PI and Lyophilized A1PI had similar average mass (~52 kDa), and both forms exhibited glycoform patterns consistent with the known banding pattern of A1PI (dominated by the M6 and M4 bands, including deconvoluted masses). Both Liquid A1PI and Lyophilized A1PI yielded average percent purity values ranging from 96% to 99% and had active content ranging from 53  mg/mL to 59  mg/mL. The PK profile of Liquid A1PI was similar to Lyophilized A1PI. Safety assessments in rabbits showed good tolerability and no test article-related changes in mortality, clinical signs, clinical pathology, body weight, food consumption, or urinalysis parameters. Following immunodepletion of antibodies that recognize Lyophilized A1PI, there were no significant differences in the anti-drug titers among animals immunized with Lyophilized A1PI and Liquid A1PI (p > 0.05), indicating that no antibodies to neoantigens were generated. Liquid A1PI and Lyophilized A1PI have similar profiles with respect to biochemical characteristics, PK, safety and neoantigenicity.

Efficacy and safety of inhaled α1-antitrypsin in patients with severe α1-antitrypsin deficiency and frequent exacerbations of COPD.

Patients with inherited α1-antitrypsin (AAT) deficiency (ZZ-AATD) and severe chronic obstructive pulmonary disease (COPD) frequently experience exacerbations. We postulated that inhalation of nebulised AAT would be an effective treatment.We randomly assigned 168 patients to receive twice-daily inhalations of 80 mg AAT solution or placebo for 50 weeks. Patients used an electronic diary to capture exacerbations. The primary endpoint was time from randomisation to the first event-based exacerbation. Secondary endpoints included change in the nature of the exacerbation as defined by the Anthonisen criteria. Safety was also assessed.Time to first moderate or severe exacerbation was a median of 112 days (interquartile range (IQR) 40-211 days) for AAT and 140 days (IQR 72-142 days) for placebo (p=0.0952). The mean yearly rate of all exacerbations was 3.12 in the AAT-treated group and 2.67 in the placebo group (p=0.31). More patients receiving AAT reported treatment-related treatment-emergent adverse events compared to placebo (57.5% versus 46.9%, respectively) and they were more likely to withdraw from the study. After the first year of the study, when modifications to the handling of the nebuliser were introduced, the rate of safety events in the AAT-treated group dropped to that of the placebo group.We conclude that in AATD patients with severe COPD and frequent exacerbations, AAT inhalation for 50 weeks showed no effect on time to first exacerbation but may have changed the pattern of the episodes.

Inhibiting the Inflammatory Injury After Myocardial Ischemia Reperfusion With Plasma-Derived Alpha-1 Antitrypsin: A Post Hoc Analysis of the VCU-α1RT Study.

BACKGROUND: Despite the benefits of reperfusion in limiting myocardial injury, the infarct size continues to expand after reperfusion because of secondary inflammatory injury. Plasma-derived alpha-1 antitrypsin (AAT) inhibits the inflammatory injury in myocardial ischemia and reperfusion. To explore the effects of plasma-derived AAT on the inflammatory response to ischemia-reperfusion injury, we analyzed time-to-reperfusion and enzymatic infarct size estimates in a post hoc analysis of the VCU-α1RT clinical trial (clinicaltrials.gov NCT01936896). METHODS: Ten patients with ST-segment elevation acute myocardial infarction (STEMI) were enrolled in an open-label, single-arm treatment study of Prolastin C, plasma-derived AAT, at 60 mg/kg infused intravenously within 12 hours of reperfusion. Biomarkers were measured serially over the first 72 hours, and patients were followed clinically for the occurrence of new-onset heart failure, recurrent MI, or death. Twenty patients with STEMI who had been enrolled in previous randomized trials with identical inclusion/exclusion criteria and had been assigned to placebo served as historical controls. RESULTS: Time to percutaneous coronary intervention and time to drug did not significantly differ between groups. AAT-treated patients had a significantly shorter time-to-peak creatine kinase myocardial band (CK-MB) values (525 [480-735] vs. 789 [664-959] minute, P = 0.005) and CK-MB area under the curve (from 1204 [758-2728] vs. 2418 [1551-4289] U·day, P = 0.035), despite no differences in peak CK-MB (123 [30-196] vs. 123 [71-213] U/mL, P = 0.71). CONCLUSIONS: A single administration of Prolastin C given hours after reperfusion in patients with STEMI led to a significant shorter time to peak and area under the curve for CK-MB, despite similar peak CK-MB values. These preliminary data support the hypothesis that Prolastin C shortens the duration of the ischemia-reperfusion injury in patients with STEMI.

Alpha 1 antitrypsin to treat lung disease in alpha 1 antitrypsin deficiency: recent developments and clinical implications.

Alpha 1 antitrypsin deficiency is a hereditary condition characterized by low alpha 1 proteinase inhibitor (also known as alpha 1 antitrypsin [AAT]) serum levels. Reduced levels of AAT allow abnormal degradation of lung tissue, which may ultimately lead to the development of early-onset emphysema. Intravenous infusion of AAT is the only therapeutic option that can be used to maintain levels above the protective threshold. Based on its biochemical efficacy, AAT replacement therapy was approved by the US Food and Drug administration in 1987. However, there remained considerable interest in selecting appropriate outcome measures that could confirm clinical efficacy in a randomized controlled trial setting. Using computed tomography as the primary measure of decline in lung density, the capacity for intravenously administered AAT replacement therapy to slow and modify the course of disease progression was demonstrated for the first time in the Randomized, Placebo-controlled Trial of Augmentation Therapy in Alpha-1 Proteinase Inhibitor Deficiency (RAPID) trial. Following these results, an expert review forum was held at the European Respiratory Society to discuss the findings of the RAPID trial program and how they may change the landscape of alpha 1 antitrypsin emphysema treatment. This review summarizes the results of the RAPID program and the implications for clinical considerations with respect to diagnosis, treatment and management of emphysema due to alpha 1 antitrypsin deficiency.

Treatment of lung disease in alpha-1 antitrypsin deficiency: a systematic review.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a rare genetic condition predisposing individuals to chronic obstructive pulmonary disease (COPD). The treatment is generally extrapolated from COPD unrelated to AATD; however, most COPD trials exclude AATD patients; thus, this study sought to systematically review AATD-specific literature to assist evidence-based patient management. METHODS: Standard review methodology was used with meta-analysis and narrative synthesis (PROSPERO-CRD42015019354). Eligible studies were those of any treatment used in severe AATD. Randomized controlled trials (RCTs) were the primary focus; however, case series and uncontrolled studies were eligible. All studies had ≥10 participants receiving treatment or usual care, with baseline and follow-up data (>3 months). Risk of bias was assessed appropriately according to study methodology. RESULTS: In all, 7,296 studies were retrieved from searches; 52 trials with 5,632 participants met the inclusion criteria, of which 26 studies involved alpha-1 antitrypsin augmentation and 17 concerned surgical treatments (largely transplantation). Studies were grouped into four management themes: COPD medical, COPD surgical, AATD specific, and other treatments. Computed tomography (CT) density, forced expiratory volume in 1 s, diffusing capacity of the lungs for carbon monoxide, health status, and exacerbation rates were frequently used as outcomes. Meta-analyses were only possible for RCTs of intravenous augmentation, which slowed progression of emphysema measured by CT density change, 0.79 g/L/year versus placebo (P=0.002), and associated with a small increase in exacerbations 0.29/year (P=0.02). Mortality following lung transplant was comparable between AATD- and non-AATD-related COPD. Surgical reduction of lung volume demonstrated inferior outcomes compared with non-AATD-related emphysema. CONCLUSION: Intravenous augmentation remains the only disease-specific therapy in AATD and there is evidence that this slows decline in emphysema determined by CT density. There is paucity of data around other treatments in AATD. Treatments for usual COPD may not be as efficacious in AATD, and further studies may be required for this disease group.

Patterns and characterization of COPD exacerbations using real-time data collection.

INTRODUCTION: Patients with chronic obstructive pulmonary disease often experience exacerbations. These events are important as they are a major cause of morbidity and mortality. Recently, it has been increasingly recognized that patients may experience symptoms suggestive of an exacerbation but do not seek treatment, which are referred to as unreported or untreated exacerbations. Symptom diaries used in clinical trials have the benefit of identifying both treated and untreated exacerbation events. METHODS: The Kamada study was a multicenter, double-blind randomized controlled trial of inhaled augmentation therapy in alpha-1 antitrypsin deficiency (AATD). A retrospective review of daily electronic symptom diary cards was undertaken from the two leading centers to identify symptomatic episodes consistent with a definition of an exacerbation. The aims were to explore the relationship between exacerbation events and classical "Anthonisen" symptoms and to characterize treated and untreated episodes. RESULTS: Forty-six AATD patients with airflow obstruction and history of exacerbations were included in the analysis. Two hundred thirty-three exacerbation episodes were identified: 103 untreated and 130 treated. Untreated episodes were significantly shorter (median 6 days; interquartile range [IQR] 3-10 days) than the treated episodes (median 10 days; IQR 5-18.25 days: P<0.001). Using logistic regression analysis, Anthonisen type and length of dyspnea were significant predictors of the treatment of an exacerbation event. CONCLUSION: Real-time electronic diary cards provide valuable information about the characterization of exacerbations. Untreated episodes are common and are significantly shorter in duration than the treated episodes. Dyspnea is the most important single Anthonisen symptom in the prediction and/or driver of treatment.

Lung Deposition of Alpha1-Proteinase Inhibitor (Human) (A1-PI[H]) Inhalation Solution Using Two Inhalation Modes of the I-neb Adaptive Aerosol Delivery (AAD) System in Healthy Subjects and Subjects with Cystic Fibrosis.

BACKGROUND: In cystic fibrosis (CF) patients, inhalation of alpha1-proteinase inhibitor (A1-PI) can prevent or slow down persistent infections and reduce the massive ongoing inflammation and excessive levels of NE that destroy the airway epithelium, leading to progressive loss of pulmonary function and death. It is essential for an efficient treatment with inhaled A1-PI that an adequate and reproducible dose is deposited within all regions of the lung. The I-neb AAD System provides two inhalation modes: the Target Inhalation Mode (TIM) and the Tidal Breathing Mode (TBM). Both were compared in this study for their efficiency to deliver A1-PI to the lungs. METHODS: This was a randomized, open label, cross-over study to investigate the lung deposition of A1-PI in 6 healthy subjects (HS) and 15 CF subjects. The primary endpoint was to evaluate the total lung deposition relative to filling dose of A1-PI inhalation solution using the I-neb AAD System in TIM and in TBM. The main secondary endpoints were extra-thoracic deposition, exhaled drug fraction, nebulizer residue, C/P ratio, and variance of pixel counts. Additional exploratory endpoints were total treatment time and the inhalation time. Radiolabeling was performed considering GMP using a commercially available sterile labeling kit. Radiolabeling was validated using NGI data acquired by gamma scintillation and UV spectrometry. RESULTS AND CONCLUSIONS: The intrapulmonary deposition (mean ± SD) in CF subjects was 47.0% ± 6.6% and 46.7% ± 10.3% in TIM and TBM, respectively, and in healthy subjects, 50.0% ± 6.7% and 54.8% ± 7.0% in TIM and TBM, respectively. TIM resulted in an approximately 40% lower treatment time (HS 6.4 min vs. 10.3 min, CF 5.3 min vs. 10.7 min) and less extra-thoracic deposition compared to TBM, and showed a higher residue of drug in the nebulizer, compared to TBM. In both groups, inhalation of a single dose of 77 mg of A1-PI was efficient, safe, and well tolerated using TIM and TBM.

SPARTA clinical trial design: exploring the efficacy and safety of two dose regimens of alpha1-proteinase inhibitor augmentation therapy in alpha1-antitrypsin deficiency.

BACKGROUND: Alpha1-antitrypsin deficiency (AATD) is an underdiagnosed genetic disorder that results in early-onset emphysema due to low serum levels of alpha1-proteinase inhibitor (alpha1-PI), leading to increased activity of tissue-damaging neutrophil elastase. Clinical outcomes of AATD may be improved by administering alpha1-PI augmentation therapy. Here, we describe the design of the ongoing Study of ProlAstin-c Randomized Therapy with Alpha-1 augmentation (SPARTA), a phase 3 trial designed to evaluate progression of lung tissue loss in patients with severe AATD receiving human alpha1-PI (Prolastin(®)-C) versus placebo, using whole-lung computed tomography (CT) densitometry. STUDY DESIGN: SPARTA is a randomized, placebo-controlled trial assessing the efficacy and safety of two separate doses of Prolastin-C (60 and 120 mg/kg) administered weekly over 3 years in patients aged 18-70 years with a diagnosis of AATD and clinical evidence of pulmonary emphysema. The primary measure of efficacy (change from baseline whole-lung 15th percentile lung density [PD15]) will be determined by CT lung densitometry measured at total lung capacity. Secondary efficacy variables will be the evaluation of severe chronic obstructive pulmonary disease exacerbations, as defined by American Thoracic Society/European Respiratory Society criteria, and PD15 of the basal lung region using CT densitometry. Adverse events will be collected and documented. CONCLUSIONS: The SPARTA trial is designed to evaluate the long-term (3-year) efficacy of 2 separate doses of Prolastin-C for the treatment of emphysema in patients with AATD. Protocol number: GTi1201. CLINICAL TRIALS IDENTIFIER: NCT01983241.

The efficacy and safety of inhaled human α-1 antitrypsin in people with α-1 antitrypsin deficiency-related emphysema.

α-1 antitrypsin deficiency (AATD) is an autosomal co-dominant condition characterized by low circulating levels of α-1 antitrypsin (AAT), a serine protease inhibitor. Significant work has been carried out in the development of AAT augmentation therapy for AATD. While the majority of this activity has focused on intravenous (iv.) augmentation, evidence of a significant clinical benefit is still debated and iv. therapy is expensive, onerous and time consuming. Inhalation therapy offers the opportunity for easier and more efficient delivery of AAT directly to the lungs with some evidence of a reduction in local inflammatory and proteolytic activity, potentially offering an alternative therapeutic option to the iv. route. There are, however, theoretical obstacles to the potential efficacy of aerosol-delivered AAT and although there have been a number of short-term studies examining inhaled AAT and its effect on lung inflammation, there has only been one long-term study to date in AATD looking at clinical outcomes, which is as yet unpublished.

[Expert statement for augmentation therapy in patients with alpha-1 antitrypsin deficiency]. / Expertenstellungnahme zur Substitutionstherapie bei Patienten mit Alpha-1 Antitrypsin-Mangel.

Augmentation therapy in Alpha-1 Antitrypsin Deficiency aims to reduce the progression of lung emphysema, to reduce exacerbation frequency, and to improve quality of life. This expert statement briefly summarizes the most important treatment studies performed in patients with Alpha-1 Antitrypsin Deficiency and severe lung emphysema. Indications and contraindications for long-term intravenous augmentation therapy with human Alpha-1 Antitrypsin are derived from the available study results. Safety issues and the controversies of this topic are discussed in detail.

α1-Antitrypsin therapy downregulates toll-like receptor-induced IL-1ß responses in monocytes and myeloid dendritic cells and may improve islet function in recently diagnosed patients with type 1 diabetes.

CONTEXT: Recent studies have implicated proinflammatory responses in the mechanism of type 1 diabetes (T1D). OBJECTIVE: Our objective was to evaluate the safety and effects of therapy with the anti-inflammatory serum protein α1-antitrypsin (AAT) on islet function and innate immunity in recent-onset patients. DESIGN AND SETTING: This was an open-label phase I trial at the Barbara Davis Center for Childhood Diabetes, University of Colorado Denver. PATIENTS: Twelve recently diagnosed subjects with T1D with detectable C-peptides were included in the study. INTERVENTION: Eight consecutive weekly infusions of 80 mg/kg of AAT were given. MAIN OUTCOME MEASURES: PATIENTS were monitored for adverse effects of AAT therapy, C-peptide responses to a mixed-meal tolerance test, and toll-like receptor (TLR)-induced cellular IL-1ß in monocytes and myeloid dendritic cells (mDCs). RESULTS: No adverse effects were detected. AAT led to increased, unchanged, or moderately reduced levels of C-peptide responses compared with baseline in 5 patients. The total content of TLR4-induced cellular IL-1ß in monocytes at 12 months after AAT therapy was 3-fold reduced compared with baseline (P < .05). Furthermore, at baseline, 82% of monocytes produced IL-1ß, but at 12 months after therapy, the level decreased to 42%. Similar reductions were observed using TLR7/8 and TLR3 agonists in monocytes and mDCs. Unexpectedly, the reduction in cellular IL-1ß was observed only 9 and 12 months after treatment but not in untreated diabetics. Improved ß-cell function in the 5 AAT-treated individuals correlated with lower frequencies of monocytes and mDCs producing IL-1ß compared with subjects without improvement of islet function (P < .04 and P < .02, respectively). CONCLUSIONS: We hypothesize that AAT may have a beneficial effect on T1D in recently diagnosed patients that is associated with downmodulation of IL-1ß.

Safety and pharmacokinetics of 120 mg/kg versus 60 mg/kg weekly intravenous infusions of alpha-1 proteinase inhibitor in alpha-1 antitrypsin deficiency: a multicenter, randomized, double-blind, crossover study (SPARK).

Augmentation therapy with the approved dose of 60 mg/kg weekly intravenous (IV) alpha-1 proteinase inhibitor (alpha1-PI), achieves a trough serum level of 11 µM in individuals with alpha-1 antitrypsin deficiency (AATD), yet this is still below the level observed in healthy individuals. This study assessed the safety and pharmacokinetic profile of weekly infusions of a 120 mg/kg dose of alpha1-PI in 30 adults with AATD. Subjects with symptomatic, genetically determined (genotypes PI*ZZ, PI*Z(null), PI*(null)(null) or PI*(Z)Mmalton) AATD were randomly assigned to weekly infusions of 60 or 120 mg/kg alpha1-PI (Prolastin-C®) for 8 weeks before crossing over to the alternate dose for 8 weeks. Adverse events (AEs) (including exacerbations), vital signs, pulmonary function tests, and laboratory assessments were recorded. Pharmacokinetic measurements included AUC0-7days, Cmax, trough, tmax, and t1/2, based on serum alpha1-PI concentrations. In total for both treatments, 112 AEs were reported, with exacerbation of COPD being the most frequent, consistent with the subjects' diagnoses. Mean steady-state serum alpha1-PI concentrations following 120 mg/kg weekly IV alpha1-PI were higher than with the 60 mg/kg dose and mean trough concentrations were 27.7 versus 17.3 µM, respectively. Dose proportionality was demonstrated for AUC0-7days and Cmax, with low inter-subject variability. The 120 mg/kg alpha1-PI weekly dose was considered to be safe and well tolerated, and provided more favorable physiologic alpha1-PI serum levels than the currently recommended 60 mg/kg dose. The effect of this dosing regimen on slowing and/or preventing emphysema progression in subjects with AATD warrants further investigation.

Expanding the clinical indications for α(1)-antitrypsin therapy.

α(1)-Antitrypsin (AAT) is a 52-kDa circulating serine protease inhibitor. Production of AAT by the liver maintains 0.9-1.75 mg/mL circulating levels. During acute-phase responses, circulating AAT levels increase more than fourfold. In individuals with one of several inherited mutations in AAT, low circulating levels increase the risk for lung, liver and pancreatic destructive diseases, particularly emphysema. These individuals are treated with lifelong weekly infusions of human plasma-derived AAT. An increasing amount of evidence appears to suggest that AAT possesses not only the ability to inhibit serine proteases, such as elastase and proteinase-3 (PR-3), but also to exert antiinflammatory and tissue-protective effects independent of protease inhibition. AAT modifies dendritic cell maturation and promotes T regulatory cell differentiation, induces interleukin (IL)-1 receptor antagonist and IL-10 release, protects various cell types from cell death, inhibits caspases-1 and -3 activity and inhibits IL-1 production and activity. Importantly, unlike classic immunosuppressants, AAT allows undeterred isolated T-lymphocyte responses. On the basis of preclinical and clinical studies, AAT therapy for nondeficient individuals may interfere with disease progression in type 1 and type 2 diabetes, acute myocardial infarction, rheumatoid arthritis, inflammatory bowel disease, cystic fibrosis, transplant rejection, graft versus host disease and multiple sclerosis. AAT also appears to be antibacterial and an inhibitor of viral infections, such as influenza and human immunodeficiency virus (HIV), and is currently evaluated in clinical trials for type 1 diabetes, cystic fibrosis and graft versus host disease. Thus, AAT therapy appears to have advanced from replacement therapy, to a safe and potential treatment for a broad spectrum of inflammatory and immune-mediated diseases.